Attachment 1 - Statement of Work.pdf

US Department of Agriculture (USDA)

Statement of Work

SECTION A – DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

A.1 Definitions/Acronyms

Vendor, Contractor, or Manufacturer – These terms are used interchangeably throughout the document...

VAC – Vaccine Antigen Concentrate sometimes referred to by industry as “For Further Manufacture.”

FFM – “For Further Manufacture” used interchangeably with VAC

F.O.B. destination – See clause 52.247-34

FUP – Final Use Product. VAC quantity is defined in terms of the minimum number of doses of finished vaccine it can yield. The finished vaccine is also referred to as FUP.

Guaranteed Shelf Life – The period of time during which the contractor guarantees their VAC will pass potency, purity and efficacy tests. During this period, any VAC that fails testing is required to be replaced at no cost to the Government. When a failure is identified, the guaranteed shelf life period immediately pauses. It is resumed upon the new VAC replacement entering storage. Due to this, contract duration may be extended as needed to ensure full coverage of guaranteed shelf life.

A.2 Embedded Hyperlinks

APHIS Forms 2007 https://www.aphis.usda.gov/sites/default/files/aphis2007.pdf

APHIS Form 2008 https://www.aphis.usda.gov/sites/default/files/APHIS_2008.pdf

21 U.S.C.151-159 https://uscode.house.gov/view.xhtml?path=/prelim@title21/chapter5&edition=prelim

9 CFR § 94.18

https://www.ecfr.gov/current/title-9/section-94.18

9 CFR Parts 101-123 https://www.ecfr.gov/current/title-9/chapter-I/subchapter-E

9 CRF § 113.3

https://www.ecfr.gov/current/title-9/section-113.47

9 CFR § 113.46

https://www.ecfr.gov/current/title-9/section-113.46

9 CFR § 113.47

https://www.ecfr.gov/current/title-9/section-113.47

9 CFR § 113.55

https://www.ecfr.gov/current/title-9/section-113.55

Title 9, Code of Federal Regulations (9 CFR), Part 114.9 (d) https://www.ecfr.gov/current/title-9/part-114/section-114.9#p-114.9(d)

A.3 Specifications

The United States Department of Agriculture (USDA), Animal and Plant Health Inspection Service (APHIS) requires the production of a foot and mouth disease (FMD) vaccine antigen concentrates (VAC), and as required, the opportunity to finish VAC into final vaccine. The USDA also requires the ability to directly purchase vaccine from the manufacturer in case of immediate need. The effective period of the contract will be equivalent to a five-year VAC and Direct purchase vaccine ordering period plus the manufacturer’s guaranteed shelf-life from date of release of the VAC and is dependent upon successful performance in the efficacy test (PD50).

The contract has the following components:

1. Production of FMD Vaccine Antigen Concentrates (VACs). Production of each FMD (VAC) serial must be purified, concentrated, and must provide a minimum of 1.0 Million doses (Quantity to be specified on orders) of vaccine (AKA final use product (FUP)). Please thoroughly review the Technical Annex (Section C) for VAC suitability. Additional FUP volume pricing may be proposed if desired. I.E. Larger batch sizes for a specific FMD VAC. This would be different from volume discounts that are based on total doses of one or more VAC type.

2. Storage of VACs on manufacturer premises

The Manufacturer will be required to store and guarantee VAC for the duration of shelf-life from date of release to bank. VAC storage requirements are outlined in the Technical Annex. (Section C)

3. Performance of quality control testing, and reporting of quality control testing results during the storage period.

The Contractor must submit documentation on the manufacture, formulation, quality control and storage of the VAC(s) as detailed in the Technical Annex. (Section C)

4. Submission of samples upon request under the conditions outlined in the Technical Annex (Section C) This task includes the periodic submission of test samples to USDA APHIS VS FADDL Vaccine Banks upon request for safety, potency and efficacy testing. Please see Technical Annex (Section C) for further details regarding vendor testing requirements and information about the testing performed by USDA.

5. Finish VAC into final vaccine (AKA final use product or FUP) if required.

Upon request from USDA, the vaccine(s) will be prepared using one or more of the VACs held by USDA, produced under this contract.

6. Direct purchase of finished vaccine from manufacturer.

Under the contract, USDA may make direct purchases of finished vaccine from manufacturer in case of immediate need. This would exclude the need for long-term storage.

A.4 Specifications/Milestones for Component 1: Production of FMD Vaccine Antigen Concentrates (VACs)

The Contractor will be responsible for the production of a specified VAC, with the capacity to yield a minimum 1.0 Million doses of deliverable finished vaccine. Actual quantities will be specified on individual orders. Delivery timelines will be determined prior to order placement to ensure vendors have sufficient production lead time.

A.5 Shipment/Delivery

All shipping and delivery costs associated with delivery of finished vaccine to any international airport in the U.S, as designated at time of order, must be included in the unit price of the VAC conversion cost. Sample shipping and delivery costs to USDA at Plum Island, NY or Manhattan, KS for testing must be included in the unit cost of the VAC. Further details regarding the delivery and shipment terms for finished vaccine and sample submissions is included in the Technical Annex. (Section C)

Contractor may be invited to send representative(s) to participate in USDA Veterinary Services table-top exercises (TTX). In the event direct attendance is not feasible, teleconference capability is anticipated. These exercises are not mandatory but highly encouraged. Expenses incurred as a result of attendance of these exercises are the sole responsibility of the contractor.

Regarding finished vaccine, when a contract is awarded, the Contractor agrees to provide Material Safety Data Sheets (MSDS) to the Contracting Officer’s Representative (COR) and the National Veterinary Stockpile (NVS).

The Government may require finished vaccine shipments to be imported through any international airport in the United States. Contractor must use the most time efficient flight route from the country of manufacture or finishing. Notifications of shipment must be made to the individuals specified on the order.

A.6 End of VAC Guaranteed Shelf Life/End of Period of Performance

At the end of the guaranteed shelf-life, the government requires the following options:

Option 1: Formulation of VAC into vaccine

The USDA could decide to request the formulation of the VAC into vaccines before the end of shelf-life and request the shipment of those vaccines to any requested International airport. At the initiative of the USDA and if the USDA is willing to make a deal with a third Party to supply them with vaccines, the Contractor will deliver the vaccine to any International airport provided regulatory and export control requirements are respected. The conversion of VAC into vaccines will be invoiced to the USDA only per Pricing Schedule in Attachment 2 – FMD VAC Price Schedule.

Option 2: VAC disposal or ownership transfer back to the Contractor

For the VAC remaining in the bank at the end of the shelf-life guaranteed period, the Contractor will take over ownership of the VAC and shall dispose of the remaining VAC at no cost to the

USDA.

Option 3: Shipment of VAC to the USDA for local storage under the following conditions:

Written waiver from the USDA regarding any Contractor liabilities related to the VAC No license granted to the USDA to use, market, distribute the VAC or any derived products Transfer of risks regarding VAC at Contractor storage site and shipment costs supported by USDA No commitment from the Contractor to manufacture finished products made from VAC No warranty provided by the Contractor on VAC or any derived products

SECTION B. CONTRACT ADMINISTRATION

B.1 Fair Opportunity / Ordering

B.1.1 Fair Opportunity

National security interests require that specific FMD VAC and vaccine purchase information will not be made available publicly. The government will require vendors to provide updated listings of the specific FMD products they offer. When the government determines specific FMD VAC or vaccine needs, only those vendors with IDIQ contracts offering the desired FMD product will be notified of the requirement. Delivery orders will be placed after comparatively evaluating the following factors to determine best value to the Government: price, delivery timelines, guaranteed shelf-life, and technical annex criteria (as described in Section C).

The Government may place orders with multiple vendors to meet necessary requirements. For purposes of evaluating price when multiple vendors offer a specific VAC serotype but not all VACs needed, total savings will be considered in addition to the per dose / per year of guaranteed shelf life.

B.1.2 Ordering

Delivery Orders will be placed by a USDA Contracting Officer. Prior to placement of order, the Contracting Officer will coordinate production lead times with the vendor prior to order placement.

B.2 Acceptance

B.2.1 Acceptance of VAC

Once a VAC is released by the manufacturer and after completion of all the quality control tests for safety, innocuity, potency, and purity, the contractor must deliver the VAC(s) to the storage vessels on the contractor’s premises dedicated for use by the vaccine bank identified on the order: North American Foot and Mouth Disease Vaccine Bank (NAFMDVB) or National Animal Vaccine and Veterinary Countermeasures Bank (NAVVCB).

At the time that the contractor delivers the VAC(s) into storage, the contractor must also include the VAC samples for safety testing, innocuity testing, 146S stability testing, and the preparation of trial blend vaccines. These ancillary VAC samples are to be stored together with the VAC.

The VAC identification (i.e. batch/serial number, virus strain, release date, volume) must be noted on each vial. Samples should be clearly identified in a permanent manner appropriate for liquid nitrogen storage conditions.

The USDA agrees to accept each VAC in advance of the quality control tests that may be performed by USDA as described in the Technical Annex (Section C). Documentation of the manufacturer’s testing procedures (e.g., APHIS Forms 2008), results, and certificate(s) of analysis for the VAC (also known as FFM) will be provided to the USDA APHIS FADDL Vaccine Banks.

The Center for Veterinary Biologics (CVB) reviews inactivation kinetics study reports. Study reports describe inactivation procedure and testing methods. If CVB agrees a study report supports the inactivation procedure and testing methods then those must be included in the approved Outline of Production (OOP) Sections IV and V, on file at the CVB.

The Contractor must perform inactivation (i.e., innocuity) tests on each batch/lot/serial of VAC.

Copies of safety or innocuity test results, as well as other manufacturer tests performed for VAC release, should be submitted to the CVB and USDA APHIS FADDL Vaccine Banks on APHIS Form 2008 the day of the transfer of the VAC into long-term storage at the manufacturer. The Contractor’s in process (e.g. OOP Section IV) inactivation kinetics and innocuity test results must be provided when requested.

Testing conducted by USDA APHIS will be considered as the final official results. In the event that the tests performed by USDA APHIS indicate a particular VAC covered under this contract does not meet the requirements for purity, safety, efficacy, or potency, the contractor must replace the VAC free of charge in a reasonable time period, so not to exceed twelve (12) months after notification of the results of the investigation into the root cause of the failure as detailed in the Technical Annex (Section C). If VAC fails a PD50 test, the manufacturer will be required to issue a $120,000.00 credit on future purchases to cover the cost of the failed test (See technical annex for additional details). The PD50 test may be repeated on the replacement VAC. Each batch of VAC will be subject to a PD50 test. This includes replacement VAC. Please review the technical annex (Section C) for further details.

At the time of transfer, the manufacturer will send a report of the transfer indicating the serotype, virus strain, the serials or batch numbers, the volume or weight of VAC in the vessel, and the date the VAC was produced to USDA APHIS FADDL Vaccine Banks.

The government reserves the right to inspect the contractor in accordance with Section VI:

Inspections of the technical annex (Section C). Typically, inspections are conducted by a team led by a representative from APHIS. At the government’s request, inspections will occur during regular business hours with a minimum 48-hour notice communicated to the vendor prior to inspection dates. The manufacturer will provide a paper copy of the full inventory for each bank separately listing all VAC batches, with the associated order number (126395XXFXXXX), its current guaranteed shelf life end date, with locations of all vessels of owned VAC and samples for that batch. NAFMDVB and NAVVCB owned material shall be stored separate from each other and any other material not owned by USDA/NAVVCB/NAFMDVB. Proper material and marking methods ensuring identification markings are not damaged and remain readable will be used (I.E. metal tags with engraving).

B 2.2 Acceptance of Finished Vaccine

Finished vaccine acceptance will occur upon delivery to the destination International Airport designated at time of order.

B.3 Period of Performance / Ordering Period

The ordering period for VAC and Direct Purchase Vaccine orders is five years from date of award. The ordering period for VAC finishing must be equivalent to the manufacturer guaranteed shelf-life of the VAC from the date the Contractor’s quality assurance (QA) or qualified person (QP) releases the VAC and dependent upon successful performance in the required testing further detailed in the Technical Annex (Section C). In the event of testing failure, it may become necessary for the period of performance to be amended by contract modification to ensure finishing and storage of VAC for the entirety of guaranteed shelf-life. The time passed between acceptance and notification of a PD50 failure will count towards the guaranteed shelf life of the VAC. Time to produce and replace said VAC will not count towards the guaranteed shelf life. The government reserves the right for VAC that has failed PD50s to require additional terms at the task order level subject to mutual agreement.

Note that the purpose for all contract years beyond year five is to allow for the possible finishing of the vaccine during its guaranteed shelf life and to ensure the contract terms cover the full storage life. New contracts are likely to be needed every five years to allow for new purchase of VAC and direct purchase of vaccine.

B.4 Invoicing and Payment

The vendor must submit invoices to the identified program POCs and Contracting Officer specified in the task order in order for payment. Once confirmed, invoice will be submitted to IOAT (FMMI) IOAT@usda.gov to be manually inputted in the Finance System for electronic payment to vendors bank unless vendor Sam.gov registration includes a U.S. Bank account. If vendor registers a U.S. bank account, invoicing instructions for the utilization of IPP.gov would be added to any resulting contract.

SECTION C. TECHNICAL ANNEX

C.1 Section 1: Regulatory requirements, Documentation, and Information

C.1.1 Outlines of production (OOP)

The Contractor must submit two outlines of production to APHIS Center for Veterinary Biologics (CVB): one outline for further manufacture (FFM) production of each vaccine antigen concentrate (VAC) offered, and one outline for the finishing of the VAC to a final use product (aka FUP or finished bottled labeled vaccine). All outlines of production must conform to Title 9, Code of Federal Regulations (9 CFR), Part 114.9 (d). Laws, regulations, and guidance related to all aspects and requirements for the use of veterinary vaccines in the United States are available through the USDA-APHIS-VS-CVB webpage.

C.1.2 Requirements for product license and permitting

The Contractor must comply with the standards set forth by the Virus-Serum-Toxin Act (21 U.S.C.151-159) and the regulations promulgated from this Act as listed in 9 CFR Parts 101-123.

These regulations were promulgated to ensure that biologic products offered for sale or use in the United States meet requirements for purity, safety, potency, and efficacy.

Vaccines must be eligible for a product license or a permit for distribution and sale in the United States. If a license or permit for distribution and sale has not yet been issued, then eligibility will be considered if the Contractor is making a good faith effort to obtain a license or permit for distribution and sale as demonstrated by its submissions to the CVB including a license or permit application, Outline of Production (OOP), safety data, applicable master seed virus and propagation cell line data, applicable National Environmental Protection Act data, reasonable expectation of efficacy data and facility documents (blueprints, plot plans, plot plan legends) that demonstrate the Contractor has a suitable manufacturing facility. Once obtained, a license or permit for distribution and sale must be maintained throughout the life of the antigen. The Contractor must designate representatives (e.g., designated liaison) in the United States who can be contacted regarding licensing/permitting questions and issues. Submissions to CVB may be shared with the NAVVCB and NAFMDVB and its Canadian representatives unless the Contractor provides sufficient justification regarding why some submissions should not be shared.

C.1.3 Ingredients of animal origin

The contractor certifies that all materials of animal origin that are used in the production of foot and mouth disease (FMD) VACs and vaccines are sourced exclusively from countries whose bovine spongiform encephalopathy (BSE) status is either no risk or low risk as defined by the USDA/APHIS/VS National Center for Import-Export (NCIE) and 9 CFR § 94.18. The Contractor’s OOP must describe the source, including vendor and country of origin, for all animal origin ingredients used in the production of FMD VACs and vaccines.

C.1.4 Personnel requirements

The Contractor must have adequately trained personnel, sufficient production equipment and instrumentation for quality control, and possess the production expertise (including pilot serial production expertise) and capacity necessary to meet the needs of USDA, NAFMDVB and NAVVCB. The Contractor’s manufacturing facility must be inspected by the USDA and determined adequate for the purpose of consistently manufacturing high quality FMD vaccines.

A list of Key personnel and their qualifications must be filed with the CVB (APHIS Forms 2007), NAVVCB and NAFMDVB; changes in key personnel must be reported within 2 months.

C.2 Section II: Testing by the Manufacturer

C.2.1 Identification and Purity of the Master Seed Virus Strain

Strain identity and purity of the master seed virus (MSV) must be verified by procedures acceptable to APHIS. The results of the strain identity and purity testing must be provided by the contractor to USDA (APHIS) by email to the FADDL Vaccine Banks Manager at the time of VAC order. The Contractor must provide USDA (APHIS), with a list of MSVs which have been tested and approved by USDA (APHIS) for use in production, and a separate list of MSV which are used to prepare commercial vaccines but have not yet been approved by USDA (APHIS).

C.2.2 Extraneous agents in Master Seed Virus and Master Cell Stocks

MSVs must be tested for extraneous agents by procedures acceptable to USDA APHIS.

Approved MSVs will be included in the OOP on file at the CVB.

Master Cell Stock (MCS) must be tested by procedures acceptable to USDA (APHIS). Approved MCSs will be included in the OOP on file at the CVB.

C.2.3 Sterility Testing

MSVs and MCSs must be tested by the contractor for extraneous viruses, bacteria (including Mycoplasmas), and fungi according to procedures acceptable to USDA (APHIS) and described in OOPs on file at CVB.

C.2.4 Inactivation Studies

Validation of the inactivation procedure must be conducted in accordance with Veterinary Services Memorandum (VSM) 800.117, Guidance for Inactivation, or otherwise acceptable to USDA (APHIS). Inactivation kinetics study data are presented to CVB and NAVVCB / NAFMDVB as applicable for approval. VSM 800.117 may be viewed at:

https://www.aphis.usda.gov/animal_health/vet_biologics/publications/memo_800_117.pdf

C.2.5 Innocuity Testing

The results of inactivation (i.e. innocuity) testing to confirm complete inactivation must be reported on APHIS Form 2008 for each FFM (i.e. VAC) serial. In FFM OOP, sections IV or V, describe the inactivation confirmation test procedure, the test validity criteria, and the criteria for satisfactory result.

Contractors must submit APHIS Forms 2008 for each serial/lot/batch of VAC (i.e. FFM) accepted by the USDA APHIS. If the USDA APHIS orders FUP then the serial/lot/batch number for each owned and tested VAC that is used to manufacture FUP must be included on the APHIS Form 2008 submitted for the FUP. All FFM OOP section V results must be reported to CVB and

NAVVCB or NAFMDVB on APHIS Form 2008; virus inactivation kinetics and innocuity test results must be reported to USDA APHIS.

C.2.6 Quantification of 146S FMD Capsids and VAC inferred Stability Testing

The concentration (in μg/ml) of 146S FMD viral particles in each VAC will be determined by the contractor and reported to USDA APHIS NAVVCB or NAFMDVB. The 146S antigen content of the VAC must be sufficient for the manufacture of the number of deliverable doses stipulated in the contract at the µg/dose of 146S described in the OOP for each of the strains.

Each year, the contractor must determine the stability of the VAC by measuring the 146S concentration in density gradients or other validated methods accepted by USDA. The in vitro tests must result in a report, provided to USDA APHIS FADDL Vaccine Banks, detailing the 146S content of the VACs in samples tubes stored with the VACs.

C.2.7 In Vivo/In Vitro Potency Testing

The contractor will perform an in vivo/in vitro potency test by vaccinating at least five head of cattle with a pilot serial (AKA small batch or pilot/trial blend vaccine) using the VAC in question and titrating antibody levels by a Virus Neutralization Test (VNT) with serum taken from the test cattle at 21 days post-vaccination, and the procedure must be described in their OOP. The potency of the vaccine will be determined by VNT and relational potency tables before VAC batch release (T0).

Subsequent in vivo inferred stability and potency tests must be performed at T0+2.5 years, T0+5, and T0+7.5 years of VAC storage. This testing will provide results on the inferred stability of the VAC(s) and the potency of the VAC(s) by means of inoculation with a pilot serial prepared from the accessory VAC samples in four (4) head of cattle performing VNTs using serum taken 21 days post-vaccination for each group. These latter testing results will be compared with those obtained from the initial potency test (T0). In the case of a VNT showing unsatisfactory results, the Contractor must propose a suitable remedy to ensure compliance with the guarantee given such as replacement of the VAC at no cost to APHIS. The USDA/NAVVCB/NAFMDVB may also conduct parallel potency testing using the PD50 to compare with the VNT potency results.

C.2.8 Testing reports – Documentation of the VAC

Documentation of the testing procedures, results, and certificate(s) of analysis for the VAC will be provided to the USDA APHIS FADDL Vaccine Banks.

The virus inactivation and innocuity test results, as well as other manufacturer’s tests performed for the VAC release, must be e-mailed to USDA APHIS NAVVCB or NAFMDVB the day of the transfer of the VAC into long-term storage at the manufacturer.

Results of the annual determination of the antigenic mass 146S, and the virus neutralization titers at Time (T)0 and then every 2.5 years for the duration of the guaranteed shelf life, must be reported to USDA APHIS FADDL Vaccine Banks Manager within two months of the completion of the tests.

C.3 Section III: Testing Completed by USDA APHIS or NAVVCB/NAFMDVB

C.3.1 Extraneous Agents testing

Government may perform testing for the detection of extraneous agents in MSV samples provided by the manufacturer according to 9 CFR § 113.55, 9 CFR § 113.46, 9 CFR § 113.47 and other procedures deemed appropriate by APHIS.

C.3.2 Nucleotide Sequencing

The Government may choose to characterize the vaccine virus master seed, the challenge virus, the VAC, and pilot serial preparations by nucleotide sequencing. The sequence information derived from these samples (except for the challenge virus) will be considered to be proprietary and therefore Proprietary Business Information (PROPIN) and will not be disclosed by the NAVVCB or NAFMDVB Bank Managers or any USDA officer to other parties without the consent of the Contractor. The sequence information generated from the MSV will be used to verify the identity of the VAC strain and as a guide for antigen selection along with serological vaccine matching.

Materials to be supplied by the Manufacturer for Nucleotide Sequencing

An aliquot of Master Seed Virus An aliquot of Challenge Virus An aliquot of the VAC A pilot serial Vaccine

C.3.3 Innocuity Testing

Tests for inactivation (innocuity test) may be conducted on the VAC using a sample of bulk harvest fluids taken after the inactivation period. The protocol for this test is to inoculate three tissue culture flasks of BHK cells, or other susceptible cells, with a proportion of the batch of bulk antigen representing at least 200 dose equivalents of the original harvest fluids taken immediately after inactivation. Examine cultures at 48 hours for cytopathic effect (CPE) and, if negative, perform two successive subcultures with 50 mL per culture of harvested fluid from the preceding culture, and re-examine at 48 hours after each sub-culture. Observing CPE for any reason designates a failure of innocuity testing.

Materials to be supplied by the Manufacturer for Innocuity Testing (Refer to Section IV):

An aliquot of VAC from bulk harvest fluids taken after inactivation

C.3.4 Safety Testing in Cattle

The government may perform a safety test on each VAC for the purpose of confirming virus inactivation. For this test, 0.1 ml of the raw VAC is inoculated via an intradermolingual route into 20 separate sites of each tongue of three (3) susceptible cows. The inoculated cattle will be observed for 21 days. If lesions consistent with FMD are observed (e.g. vesicle formation), the VAC is considered unsatisfactory. Sera will be collected from each cow prior to inoculation, and

21 days after inoculation and then analyzed for FMD antibodies to non-structural proteins (NSP) using a validated ELISA test.

Materials to be supplied by the Manufacturer for Safety Testing (Refer to Section IV):

An aliquot of VAC

C.3.5 Sterility Testing

The Government may perform identity and purity tests on master-seed viruses, challenge viruses, and VAC samples, and sterility tests on pilot serials.

C.3.6 Quantification of 146S Antigen Content of the VAC

Each year, the contractor must determine the stability of the VAC by measuring the 146S concentration in density gradients or other validated methods accepted by the USDA (APHIS), NAFMDVB or NAVVCB.

The Government may repeat the 146S test on additional auxiliary VAC samples for quality control verification through sucrose gradient analysis or high-performance liquid chromatography (HPLC).

For sucrose gradient analysis: 1.0 ml of a 1:2 dilution of clarified VAC will be layered on top of a 55%/15% sucrose gradient in an ultracentrifuge tube and then centrifuged at 41,000 rpm for 2.5 hours. The concentrated fractions will appear as bands inside the density gradient; these band fractions will be collected from the gradient and placed into cuvettes where the 146S full virions are detected by spectrophotometry at 259 nanometers and antigen concentration calculated based on the extinction coefficient for FMD.

For HPLC: 100µL of clarified VAC (chloroform extraction and nuclease digestion) will be separated through size-exclusion chromatography, using a TSKgel® G4000PWXL column, and 146S viral particle measured through absorption at 254nm.

The 146S concentration of the VAC must be stable for the minimum guarantee period and any variance in testing results must be within expected tolerance limits as defined by the contractor at the time of production for each VAC. If however, during a minimum guarantee storage period there is significant variation in the testing results that are consistently outside the defined tolerance limits; or there is a decline in the 146S concentration of the VAC resulting in insufficient antigenic mass to finish the contracted number of doses at the concentration and potency determined in the outline of production, then the manufacturer must replace the VAC at no cost to USDA.

Materials to be supplied by the Manufacturer for 146S Content of the VAC (Refer to Section IV):

An aliquot of VAC

C.3.7 In Vivo Potency Testing - Protective Dose 50% (PD50) in Cattle

The potency of the VAC will be determined by a PD50 study. The PD50 will be performed by testing a pilot serial prepared by the contractor using auxiliary samples of the VAC that have been stored together with the bulk VAC and prepared in a manner identical to the finished vaccine described within this contract. The VAC may be tested at any time during the minimum guaranteed storage period.

All animals used for this test are susceptible cattle meeting the following criteria:

are at least 6 months of age and weigh a minimum of 350-450 pounds;

sourced from herds known to be free of FMD;

have not been vaccinated for or exposed to FMD;

and are free of topotype-specific FMD antibodies at the final 1:10 dilution in a virus neutralization test using 50 to 300 TCID50 of virus.

There will be a total of 17 animals in the study with 15 animals divided into three groups of five that will be vaccinated with graduated doses of vaccine per group, and a group of two cattle that will be sham vaccinated to serve as control animals. The amount of antigen each group of 5 cattle receives will vary by administering different volumes of vaccine. The vaccine will be administered via the intramuscular route and the injection scheme is as follows:

5 cattle will receive 2.0 ml of vaccine;

5 cattle will receive 0.5 ml of vaccine;

5 cattle will receive 0.125 ml of vaccine;

and the 2 sham-vaccinated control cattle will receive 2.0 ml of sterile water.

Blood samples will be collected from each of the groups on day 0, 7, 14, and 21 post-vaccination.

Twenty-one days post vaccination, the 15 animals vaccinated for FMD and the 2 sham vaccinated control animals will be challenged with the homologous virulent FMD virus corresponding to the VAC being tested but having a different passage history than the virus used to manufacture the vaccine thus retaining wild-type virulence. The challenge virus will be given by the intradermolingual route at four (4) sites on the tongue with a total of 10,000 BID50 (50% bovine infectious doses, as determined previously by cattle titration, or equivalent). Vaccinates and controls must be observed for 8 days post challenge and examined for lesions of FMD. The group of animals vaccinated with 1/16 dose (0.125 ml) will be transferred to a separate room immediately prior to challenge for the 8-day observation period. At 8 days post challenge, a final blood sample will be taken from all groups of cattle and subjected to a DIVA ELISA test.

This in vivo titration of the vaccine will ascertain its potency by determining the titer of virus-neutralizing antibodies to the strain of FMD virus in the pilot serial. For a valid test, both sham vaccinated control animals must develop generalized signs of FMD with lesions on at least three of the feet.

Unprotected animals must show lesions at sites other than the tongue. From the number of protected and unprotected animals in each group, the 50% protective dose (PD50) for the pilot serial is calculated. To qualify as a successful test, the vaccine must contain at least 6 PD50 per 2 ml dose. If a VAC fails the PD50 test, upon request by the NAVVCB or NAFMDVB, the manufacturer must replace the VAC or its antigenic equivalent at no cost to USDA within 12 months of the conclusion of an investigation into the root cause of the failure. The investigation must be limited to no more than 12 months. The manufacturer must reimburse the government the cost of the failed PD50 test in the amount of $120,000. If the Government does not purchase subsequent VAC, these credit(s) must be reimbursed to USDA in the form of monetary compensation.

A validated DIVA test for antibody to 3ABC or other diagnostically relevant NSPs must be negative at 21 days post vaccination. If antibodies to FMD neutralizing antigens or extraneous antibodies generated by FMD antigens other than 3D are found in the sera of cattle 21 days after vaccination, the VAC is considered as unsatisfactory. In the case of an unsatisfactory results of the test and each time there is a question of quality of the VAC, USDA will notify the manufacturer of the test results no more than 30 days after the failure of the NSP test.

Materials to be supplied by the Manufacturer for Potency Testing (Refer to Section IV):

An aliquot of Challenge Virus A Trial Blend Vaccine

C.3.8 Test for Antibodies to Non-Structural Protein (NSP)

A test for antibodies against NSPs will be conducted on serum from cattle at the end of the safety test (21 dpi) and in the potency tests at 21 days post vaccination, by using a validated DIVA test.

If antibody to NSP is found in the sera of cattle after inoculation of the VAC, or in animals vaccinated with a corresponding pilot serial prior to challenge, the ELISA test will be repeated.

If NSP antibody presence is confirmed, the VAC is unsatisfactory. If a VAC fails to meet the requirements and results in animals seroconverting and demonstrating the NSPs specified in the validated DIVA test, USDA will notify the manufacturer of the results of the test and provide test data. Upon request by the Government, the contractor must replace the VAC at no cost to USDA within 12 months.

C.3.9 Challenge Virus

The Government, may choose to characterize the challenge virus preparation provided by the contractor by nucleotide sequencing and titration of infectivity in bovine tongue and cell cultures. If unsatisfactory results are found such as non-viable virus, failure to produce generalized foot lesions in at least three feet in each control animal, or challenge virus which is not homologous to the corresponding VAC, then the contractor will be required to furnish another shipment of the challenge virus. If the manufacturer cannot provide a bovine harvested challenge virus preparation then a low passage original field virus homologous to the vaccine strain can be supplied for propagation and titration in cattle.

Materials to be supplied by the Manufacturer for Challenge Virus evaluation (Refer to Section IV):

An aliquot of Challenge Virus

C.4 Section IV: Samples provided by Manufacturer to Government

C.4.1 VAC and Sample identification

Each cryopreservation vessel must be clearly identified with a NAVVCB or NAFMDVB label as appropriate; and labels affixed to the individual VAC containers must bear the following identifying information:

the serotype/subtype of virus;

the serial number of the batch;

volume of antigen;

and the date the VAC was released

Identifying labels must be affixed to the VAC container which are permanent, indelible, and impervious to the effects of moisture and the conditions of ultra-cold storage, such as an etched or stamped metal tag bearing the required identifying information as designated above.

C.4.2 Pilot Serial

The following information regarding the formulation of a pilot serial must be provided by email at the time of shipping to the Government:

the volume and concentration in micrograms/ml (based on the results of the 146S testing) of the antigen;

the volume and type of buffers;

and the volume of mineral oil and emulsifying agents.

The pilot serial label must contain:

batch/serial number;

the dose volume; the valence of the vaccine;

the true name of the product, including serotype(s)/subtype(s) of the vaccine strain(s);

the date of manufacture;

the date of expiration;

the storage temperature 2°C-8°C the total volume in the vial.

Sample Requirements

Sample Type

Sample Volume

Number

Samples

Sample Characteristic and Anticipated Delivery

Master Seed Virus

1.0 ml 10 Titer of at least 100,000 cell culture infectious dose (CCID50/ml);

Upon request within 6 months

Antiserum 1.0 ml 15 Capacity to neutralize a titer of at least 100,000 CCID50/ml;

Upon request within 6 months

Challenge Virus*

1.0 ml 10 Each vial must contain a minimum of 106 BID50/ml (or equivalent); challenge virus must have a different passage history from the Master Seed Virus and VAC;

and the challenge virus must retain wild-type virulence;

Within 6 months of VAC delivery

VAC 8.0 ml 20 VAC used for 146S determination, identity, safety, and innocuity;

Delivered annually, based on VAC delivery date

Pilot serial 300 doses or 600 ml

10 Each pilot serial must contain 300 doses;

Delivery will occur by request

*This virus will be propagated by the Government, in tissue culture for use in virus neutralization tests.

This section describes the samples the manufacturer must provide for confirmation of purity, safety, potency, and efficacy.

C.4.3 Master Seed Virus Samples

The manufacturer will provide ten vials of MSV. The MSV titer must be in the range of 100,000 CCID50/ml. These samples may be used to confirm the results of extraneous agents testing performed by the manufacturer and nucleotide sequencing for confirmatory identification.

C.4.4 Antiserum Samples

The manufacturer will provide fifteen 1.0 ml vials of antiserum produced against an MSV homologous virus capable of neutralizing at least 100,000 CCID50/ml of virus. The antiserum must be produced with a strain of virus of the same subtype as the MSV, but with a history of origin different than that of the master seed virus.

C.4.5 Challenge Virus Samples

The manufacturer will provide ten vials of virulent FMD challenge virus each adequate to challenge inoculate 20 cattle. Naive animals inoculated in the tongue with 104 BID50 (or equivalent) should develop FMD lesions in at least 3 feet within 8 days post inoculation. The virus must be derived from an acceptable known reference stock of the same serotype retaining its wild-type virulence. Origin and passage history of the challenge virus will be submitted together with the challenge virus material.

C.4.6 VAC Samples for 146S

A total of 20 vials x 8.0 ml each must be taken and stored along with the VAC. The Contractor must supply one vial x 8.0 ml of VAC to the Government, for 146S antigenic mass determination at the time of QA release and delivery to the storage at the liquid nitrogen freezer. Information with the micrograms of 146S antigen content per ml will be provided together with samples. The remaining nineteen (19) 8.0 ml samples must be kept with the VAC and one vial shipped once every year for the next 4 years to the Government, for 146S determination. The rest of the samples must be kept as retention samples or in case the tests need to be repeated.

C.4.7 VAC Samples for Pilot Serial Vaccine, Safety Test, and Innocuity Test

Ten antigen samples of each VAC, each sample containing a volume adequate to prepare a pilot serial of 300 doses of finished vaccine and to perform the 146S particle determination. One of these samples may be used for the safety test in cattle and innocuity test in vitro.

C.4.8 Pilot Serials

The manufacturer will be required to prepare up to 10 pilot serials over the guaranteed period for vaccine efficacy studies. Each pilot serial will be for 300 bovine doses (600 ml). Although small scale, the pilot serials must use the same formula, same ingredients and sources, and similar production methods and equipment as commercial scale production.

The Contractor will produce and deliver a pilot serial and will send information on the formulation indicating volume of antigen concentrate, volume of buffers, and volume of mineral oil and emulsifying agents. Pilot serial production and test records (e.g., APHIS Form 2008) must be provided to the Government, if the records are requested.

The Contractor must prepare a representative pilot serial (containing at least 300 doses) at the Contractor's vaccine finishing facility in accordance with the Contractor's approved OOP for finishing vaccines. The Contractor must perform 146S particle determinations on the VAC sample used for the pilot serial production and report this concentration in μg per dose to the Government. The finished pilot serial must be delivered to the Government, within four months of request.

C.4.9 Extra Samples

Besides the samples described in this section, the manufacturer has to be cognizant and comply with the 9 CRF § 113.3 sampling of biological products. The Government, in rare occasions, may collect extra test samples of each VAC when needed to retest in case of inconclusive results, to confirm the Contractor's results and perform acceptance tests.

C.4.10 Sample Labelling

The label of each sample must be printed in a legible, permanent, and cryo-stable manner and must include:

Type of sample, i.e. MSV, challenge virus, VAC, etc., Batch number, Volume, Concentration or titer, if possible (or supplied at a later date), and VAC samples must display the strain identification code

For older samples with no label, supporting documentation must accompany the shipment that includes the specific information that would have been on a label otherwise.

C.5 Section V: Shipping of Samples and Finished Vaccine

C.5.1 Delivery Requirements for Samples

Export approvals, including licensing and permits, must be in place prior to shipment.

The following instructions must be followed for any shipment of master seed virus, master cell stocks, VAC samples, pilot serials, or challenge viruses sent to the FADDL at the Plum Island Animal Disease Center or the National Bio and AgroDefense Facility. For shipment of finished vaccine refer to F.5.2 below.

1. Shipment of foot-and-mouth disease virus (FMDV) and other foreign animal disease (FAD) agents must be under a select agent transfer authorization (SATA) issued by the US CDC/APHIS. All other non-select agent biological materials of livestock or poultry origin, must enter the United States under a US Department of Agriculture import permit.

A copy of the provided SATA or import permit must be placed in an outside envelope attached to the shipping box for easy access upon arrival inspection.

2. For packaging instructions see the diagrammed instructions attached to the permit. Do not use aqueous ice; use either dry ice or frozen (gel) packs. Indicate on the outside of the package the temperature at which the materials are to be stored (e.g. 4C, -20C, -70C, or liquid nitrogen). Also, indicate if the materials are for diagnostic testing, or for safety testing, or reference materials.

3. All packages must be addressed as follows:

(Information to be included in award)

It is very important that the package is addressed to the US Department of Agriculture (not just USDA) to expedite clearance through US Customs.

4. Make arrangements with FADDL prior to shipping materials to ensure that there is someone available to receive the materials and immediately upon shipping, notify the FADDL Vaccine Banks Manager by email at (Information to be included in award) with the following information:

a) Airline and flight number

b) Date and time of arrival

c) Air waybill number (without this number the package cannot be located at the airport)

Notification can be made 7 days a week, 24 hours a day. If calling other than normal business hours (8:30 am to 4:15 pm Eastern standard time, Monday through Friday) call (Information to be included in award) to leave a message.

5. If possible, arrange for packages to arrive at John F. Kennedy International Airport in New York, NY or Kansas City International Airport in Kansas City, MO during the following days: Monday through Thursday.

6. Live FMDV is classified by the Federal Select Agent Program as a Tier 1 Select Agent and requires a select agent authorization (SATA) issued by CDC/APHIS. Do not ship master seed virus, master cell stocks, VAC samples, trial blends, and challenge viruses to or through any airport in the United States except:

John F. Kennedy International Airport (JFK), New York, NY unless there is no other alternative if final destination is to PIADC.

Kansas City International Airport (MCI), Kansas City, MO unless there is no other alternative if final destination is to NBAF.

If it is not possible to obtain a direct flight into JFK and the shipment enter through another point of entry such as Miami International Airport or any other port of entry, then clearly mark on the outside of the package that the shipment is to clear customs only at John F. Kennedy International Airport, New York, NY.

7. Avoid changing airline carriers at any international airport. This is important because air waybill numbers change with airline carriers; thus, increasing the chances of the shipment being lost.

8. DO NOT USE ANY COMMERCIAL EXPRESS CARRIERS (e.g. FED EX, DHL, AIRBORNE) for shipment of biological materials to FADDL. Most of these carriers enter the US through their own hub airports which are not approved international ports of entry. Packages containing restricted biological materials sent this way may be confiscated and destroyed upon arrival.

C.5.2 Conversion of Stored VAC and Delivery Requirements of Finished Vaccines

Each request of conversion of stored VAC into formulated vaccine and Free on Board (FOB) destination shipment to any U.S, Mexico or Canada International Airport will be invoiced to USDA only.

Early Release of Finished Vaccine

Finished vaccine availability from formulated VAC must be described by the Contractor in terms of maximum doses available in the minimum time period (in days) possible.

If both the NAFMDVB and NAVVCB wish to finish vaccine, the USDA will issue direction to the Contractor in writing for whether a NAFMDVB or NAVVCB order should be filled first.

Orders will be filled consecutively.

The Contractor shall be entitled to supply early release of finished vaccine prior to completion of testing provided the NAFMDVB or NAVVCB submits a signed copy of the Early Release certificate. The Contractor must provide a template of the Early Release certificate. In case of request of delivery of vaccines to multiple locations/countries, an Early Release Certificate will be required for each country.

Finished Vaccine ordering

Upon request from USDA, the Contractor shall carry out the formulation of vaccines using the stored VACs. In order to avoid errors of transmission that might result in accidental or undesired use of VAC stocks, the USDA order request shall be made to the Contractor by two different means (telephone and e-mail); the email shall include a Contractor-provided form to be delivered to Contractor contacts as defined by the Contractor. The order will be considered received by the Contractor after email receipt acknowledgment and oral contact established. The Contractor shall confirm by written notice the confirmation of bank activation request within one working day.

The USDA is under no obligation to advise the Contractor in advance of a requirement.

Delivery Orders

The Contractor shall complete the manufacture, fill the finished vaccines into vials, label and package the vaccines. Formulation, filling, labelling, packaging and control of the finished vaccines shall conform to specifications of the manufacturer's approved OOP and Quality guidelines. Any modification of these procedures must be agreed to in advance by both parties and revision of the OOP before implementation of changes. The minimum order quantity for finished monovalent or multivalent vaccine formulated from the NAVVCB or NAFMDVB VAC inventory must be defined.

Labels and Packaging

Product inserts/leaflets and box and vial labels for finished vaccines must be developed by the Contractor, in compliance with USDA APHIS regulations, and approved by the NAVVCB or NAFMDVB. The Contractor must define how finished product will be packaged (vials/box, boxes/case, case/pallet). All packing and shipping materials must be provided by the Contractor.

The finished product will be packed in cases/cartons with sufficient ice packs or other suitable material that will maintain the product's temperature at 2 to 8°C for 24 hours outside of refrigerated areas. An electronic temperature monitor must be included in each case/carton and will be checked at the vaccine final destination. This temperature monitor must be accessible to get a reading from the outside of the palletized containers without unpacking the pallet. USDA may request alternative packaging and quantities in packaging with mutual agreement.

C.6 Section VI: Inspections

The government reserves the right to inspect the Contractor. An APHIS representative or representatives will conduct inspections. At the government’s request, inspections will occur during regular business hours with a minimum 48-hour notice communicated to the vendor prior to inspection dates.

The inspections will help the USDA assess the Contractor’s ability to comply with contract requirements regarding vaccine quality, quantity and timeliness. The scope of the inspections may include, but is not limited to, the following:

Inspect the storage facilities where the Government owned…